tbuckley/cabot-search huggingface dataset:
Low-Intensity Adjuvant Chemotherapy for Breast Cancer in Older Women: Results From the Prospective Multicenter HOPE Trial
Authors: Mina S. Sedrak, Can-Lan Sun, Jingran Ji, Harvey J. Cohen, Cary P. Gross, William P. Tew, Heidi D. Klepin, Tanya M. Wildes, Efrat Dotan, Rachel A. Freedman, Tracey O'Connor, Selina Chow, Mary Ann Fenton, Beverly Moy, Andrew E. Chapman, William Dale, Vani Katheria, Nicole M. Kuderer, Gary H. Lyman, Allison Magnuson, Hyman B. Muss
Journal: Journal of Clinical Oncology (2022)

Older women with high-risk early breast cancer (EBC) benefit from adjuvant chemotherapy, but their treatment is frequently complicated by toxic side effects, resulting in dose reductions and delays. This makes it challenging for oncologists to maintain a relative dose intensity (RDI) ≥ 85%, as recommended for optimal curative-intent treatment. Understanding which women are at risk of receiving suboptimal RDI may inform treatment discussions and guide early, targeted supportive care or geriatric comanagement interventions. This was a prespecified secondary analysis of the HOPE trial, which enrolled women age ≥ 65 years with EBC initiating neoadjuvant or adjuvant chemotherapy. RDI was calculated as the ratio of delivered to planned chemotherapy dose intensity. The primary outcome was low RDI, defined as RDI < 85%. Multivariable logistic regression with stepwise selection was used to evaluate the association between baseline variables (demographic, clinical, and geriatric assessment) and low RDI. Survival probability was estimated using the Kaplan-Meier method, and the log-rank test was used to compare overall survival. Three hundred twenty-two patients (median age at diagnosis, 70 years; range, 65-86 years) were included. The median follow-up was 4 years. Sixty-six patients (21%) had a low RDI. Age ≥ 76 years (odds ratio [OR], 2.57; 95% CI, 1.12 to 5.91; P = .03), lower performance status (OR, 4.32; 95% CI, 1.98 to 9.42; P < .001), and use of anthracycline-based or cyclophosphamide, methotrexate, and fluorouracil regimens (OR, 3.47; 95% CI, 1.71 to 7.05; P < .001) were associated with low RDI. The 5-year overall survival probability was 0.80 versus 0.91 in patients with RDI < 85 versus ≥ 85%, respectively (log-rank P = .02). One in five older patients with EBC treated with standard chemotherapy received low RDI and had inferior survival outcomes. Older patients at risk for low RDI should be identified and targeted upfront before initiating chemotherapy.
Chemical induction of splice-neoantigens attenuates tumor growth in a preclinical model of colorectal cancer
Authors: Shingo Matsushima, Masahiko Ajiro, Kei Iida, Kenji Chamoto, Tasuku Honjo, Masatoshi Hagiwara
Journal: Science Translational Medicine (2022)

Neoantigen production is a determinant of cancer immunotherapy. However, the expansion of neoantigen abundance for cancer therapeutics is technically challenging. Here, we report that the synthetic compound RECTAS can induce the production of splice-neoantigens that could be used to boost antitumor immune responses. RECTAS suppressed tumor growth in a CD8 + T cell– and tumor major histocompatibility complex class I–dependent manner and enhanced immune checkpoint blockade efficacy. Subsequent transcriptome analysis and validation for immunogenicity identified six splice-neoantigen candidates whose expression was induced by RECTAS treatment. Vaccination of the identified neoepitopes elicited T cell responses capable of killing cancer cells in vitro, in addition to suppression of tumor growth in vivo upon sensitization with RECTAS. Collectively, these results provide support for the further development of splice variant–inducing treatments for cancer immunotherapy.
Data-driven identification of post-acute SARS-CoV-2 infection subphenotypes
Authors: Hao Zhang, Chengxi Zang, Zhenxing Xu, Yongkang Zhang, Jie Xu, Jiang Bian, Dmitry Morozyuk, Dhruv Khullar, Yiye Zhang, Anna S. Nordvig, Edward J. Schenck, Elizabeth A. Shenkman, Russell L. Rothman, Jason P. Block, Kristin Lyman, Mark G. Weiner, Thomas W. Carton, Fei Wang, Rainu Kaushal
Journal: Nature Medicine (2022)

Abstract The post-acute sequelae of SARS-CoV-2 infection (PASC) refers to a broad spectrum of symptoms and signs that are persistent, exacerbated or newly incident in the period after acute SARS-CoV-2 infection. Most studies have examined these conditions individually without providing evidence on co-occurring conditions. In this study, we leveraged the electronic health record data of two large cohorts, INSIGHT and OneFlorida+, from the national Patient-Centered Clinical Research Network. We created a development cohort from INSIGHT and a validation cohort from OneFlorida+ including 20,881 and 13,724 patients, respectively, who were SARS-CoV-2 infected, and we investigated their newly incident diagnoses 30–180 days after a documented SARS-CoV-2 infection. Through machine learning analysis of over 137 symptoms and conditions, we identified four reproducible PASC subphenotypes, dominated by cardiac and renal (including 33.75% and 25.43% of the patients in the development and validation cohorts); respiratory, sleep and anxiety (32.75% and 38.48%); musculoskeletal and nervous system (23.37% and 23.35%); and digestive and respiratory system (10.14% and 12.74%) sequelae. These subphenotypes were associated with distinct patient demographics, underlying conditions before SARS-CoV-2 infection and acute infection phase severity. Our study provides insights into the heterogeneity of PASC and may inform stratified decision-making in the management of PASC conditions.
Microfluidic‐Assisted Production of Gastro‐Resistant Active‐Targeted Diatomite Nanoparticles for the Local Release of Galunisertib in Metastatic Colorectal Cancer Cells
Authors: Chiara Tramontano, João Pedro Martins, Luca De Stefano, Marianna Kemell, Alexandra Correia, Monica Terracciano, Nicola Borbone, Ilaria Rea, Hélder A. Santos
Journal: Advanced Healthcare Materials (2022)

The oral route is highly desirable for colorectal cancer (CRC) treatment because it allows concentrating the drug in the colon and achieving a localized effect. However, orally administered drugs are often metabolized in the liver, resulting in reduced efficacy and the need for higher doses. Nanoparticle-based drug delivery systems can be engineered to prevent the diffusion of the drug in the stomach, addressing the release at the target site, and enhancing the efficacy of the delivered drug. Here, an orally administrable galunisertib delivery system is developed with gelatin-covered diatomite nanoparticles targeting the ligand 1-cell adhesion molecule (L1-CAM) on metastatic cells, and further encapsulated in an enteric matrix by microfluidics. The gastro-resistant polymer protects the nanoparticles from the action of the digestive enzymes and allows for a sustained release of galunisertib at the intestinal pH. The efficacy of antibody-antigen interactions to drive the internalization of nanoparticles in the targeted cells is investigated in CRC cells expressing abnormal (SW620) or basal levels (Caco-2, HT29-MTX) of L1-CAM. The combination of local drug release and active targeting enhances the effect of the delivered galunisertib, which inhibits the migration of the SW620 cells with greater efficiency compared to the free drug.
Racial and Ethnic Disparities in Cervical Cancer Incidence, Survival, and Mortality by Histologic Subtype
Authors: Camryn M. Cohen, Nicolas Wentzensen, Philip E. Castle, Mark Schiffman, Rosemary Zuna, Rebecca C. Arend, Megan A. Clarke
Journal: Journal of Clinical Oncology (2022)

We conducted an integrated population-based analysis of histologic subtype-specific cervical cancer incidence, survival, and incidence-based mortality by race and ethnicity, with correction for hysterectomy prevalence.
Safety and Efficacy of MEDI0457 plus Durvalumab in Patients with Human Papillomavirus–Associated Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma
Authors: Charu Aggarwal, Nabil F. Saba, Alain Algazi, Ammar Sukari, Tanguy Y. Seiwert, Missak Haigentz, Mercedes Porosnicu, Marcelo Bonomi, Jean Boyer, Mark T. Esser, Lily I. Cheng, Sonia Agrawal, Emily C. Jennings, Nicholas M. Durham, Karl Fraser, Delphine Lissa, Maozhen Gong, Natalia Ceaicovscaia, Amaya Gascó Hernández, Rakesh Kumar
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Tumoral programmed cell death ligand-1 (PD-L1) expression is common in human papillomavirus (HPV)–associated head and neck squamous cell carcinoma (HNSCC). We assessed whether a DNA vaccine targeting HPV-16/18 E6/E7 with IL12 adjuvant (MEDI0457) combined with the PD-L1 inhibitor durvalumab could enhance HPV-specific T-cell response and improve outcomes in recurrent/metastatic HPV-16/18–associated HNSCC. Patients and Methods: In this phase Ib/IIa study, immunotherapy-naïve patients with ≥1 previous platinum-containing regimen (neoadjuvant/adjuvant therapy or for recurrent/metastatic disease) received MEDI0457 7 mg intramuscularly with electroporation on weeks 1, 3, 7, and 12, then every 8 weeks, plus durvalumab 1,500 mg intravenously on weeks 4, 8, and 12, then every 4 weeks, until confirmed progression and/or unacceptable toxicity. Coprimary objectives were safety and objective response rate (ORR; H0: ORR ≤ 15%); secondary objectives included 16-week disease control rate (DCR-16), overall survival (OS), and progression-free survival (PFS). Results: Of 35 treated patients, 29 were response evaluable (confirmed HPV-associated disease; received both agents). ORR was 27.6% [95% confidence interval (CI), 12.7–47.2; four complete responses, four partial responses]; responses were independent of PD-L1 tumor-cell expression (≥25% vs. &amp;lt;25%). DCR-16 was 44.8% (95% CI, 26.5–64.3). Median PFS was 3.5 months (95% CI, 1.9–9.0); median OS was 29.2 months (15.2–not calculable). Twenty-eight (80.0%) patients had treatment-related adverse events [grade 3: 5 (14.3%); no grade 4/5], resulting in discontinuation in 2 (5.7%) patients. HPV-16/18–specific T cells increased on treatment; 4 of 8 evaluable patients had a &amp;gt;2-fold increase in tumor-infiltrating CD8+ T cells. Conclusions: MEDI0457 plus durvalumab was well tolerated. While the primary efficacy endpoint was not reached, clinical benefit was encouraging.
Hydroxyurea ameliorates atherosclerosis in ApoE<sup>-/-</sup> mice by potentially modulating Niemann-Pick C1-like 1 protein through the gut microbiota
Authors: Xin-Yu Yang, Hang Yu, Jie Fu, Hui-Hui Guo, Pei Han, Shu-Rong Ma, Li-Bin Pan, Zheng-Wei Zhang, Hui Xu, Jia-Chun Hu, Hao-Jian Zhang, Meng-Meng Bu, Xian-Feng Zhang, Wei Yang, Jing-Yue Wang, Jing-Yu Jin, Hui-Cong Zhang, Dong-Rui Li, Jin-Yue Lu, Yuan Lin, Jian-Dong Jiang, Qian Tong, Yan Wang
Journal: Theranostics (2022)

Rationale:The efficacy and mechanism of hydroxyurea in the treatment of atherosclerosis have rarely been reported.The goal of this study was to investigate the efficacy of hydroxyurea in high-fat diet-fed ApoE -/-mice against atherosclerosis and examine the possible mechanism underlying treatment outcomes.Methods: ApoE -/-mice were fed a high-fat diet for 1 month and then administered hydroxyurea by gavage continuously for 2 months.Aortic root hematoxylin-eosin (H&E) staining and oil red O staining were used to verify the efficacy of hydroxyurea; biochemical methods and ELISA were used to detect changes in relevant metabolites in serum.16S rRNA was used to detect composition changes in the intestinal bacterial community of animals after treatment with hydroxyurea.Metabolomics methods were used to identify fecal metabolites and their changes.Immunohistochemical staining and ELISA were used for the localization and quantification of intestinal NPC1L1.Results: We showed that aortic root HE staining and oil red O staining determined the therapeutic efficacy of hydroxyurea in the treatment of atherosclerosis in high-fat diet-fed ApoE -/-mice.Serological tests verified the ability of hydroxyurea to lower total serum cholesterol and LDL cholesterol.The gut microbiota was significantly altered after HU treatment and was significantly different from that after antiplatelet and statin therapy.Meanwhile, a metabolomic study revealed that metabolites, including stearic acid, palmitic acid and cholesterol, were significantly enriched in mouse feces.Further histological and ELISAs verified that the protein responsible for intestinal absorption of cholesterol in mice, NPC1L1, was significantly reduced after hydroxyurea treatment.Conclusions: In high-fat diet-fed ApoE -/-mice, hydroxyurea effectively treated atherosclerosis, lowered serum cholesterol, modulated the gut microbiota at multiple levels and affected cholesterol absorption by reducing NPC1L1 in small intestinal epithelial cells.
Incidence and prevalence of hamstring injuries in field-based team sports: a systematic review and meta-analysis of 5952 injuries from over 7 million exposure hours
Authors: Nirav Maniar, Declan Singleton Carmichael, Jack Thomas Hickey, Ryan Gregory Timmins, Argell Joseph San Jose, Jessica Dickson, David Opar
Journal: British Journal of Sports Medicine (2022)

Objective This study aimed to systematically review and meta-analyse the incidence and prevalence of hamstring injuries in field-based team sports. A secondary aim was to determine the impact of other potential effect moderators (match vs training; sport; playing surface; cohort age, mass and stature; and year when data was collected) on the incidence of hamstring injury in field-based team sports. Design Systematic review and meta-analysis. Data sources CINAHL, Cochrane Library, MEDLINE Complete (EBSCO), Embase, Web of Science and SPORTDiscus databases were searched from database inception to 5 August 2020. Eligibility criteria Prospective cohort studies that assessed the incidence of hamstring injuries in field-based team sports. Method Following database search, article retrieval and title and abstract screening, articles were assessed for eligibility against predefined criteria then assessed for methodological quality using the Critical Appraisal Tool for prevalence studies. Meta-analysis was used to pool data across studies, with meta-regression used where possible. Results Sixty-three articles were included in the meta-analysis, encompassing 5952 injuries and 7 262 168 hours of exposure across six field-based team sports (soccer, rugby union, field hockey, Gaelic football, hurling and Australian football). Hamstring injury incidence was 0.81 per 1000 hours, representing 10% of all injuries. Prevalence for a 9-month period was 13%, increasing 1.13-fold for every additional month of observation (p=0.004). Hamstring injury incidence increased 6.4% for every 1 year of increased average cohort age, was 9.4-fold higher in match compared with training scenarios (p=0.003) and was 1.5-fold higher on grass compared with artificial turf surfaces (p&lt;0.001). Hamstring injury incidence was not significantly moderated by average cohort mass (p=0.542) or stature (p=0.593), was not significantly different between sports (p=0.150) and has not significantly changed over the last 30 years (p=0.269). Conclusion Hamstring injury represents 10% of all injuries in field-based team sports, with 13% of the athletes experiencing a hamstring injury over a 9-month period most commonly during matches. More work is needed to reduce the incidence of hamstring injury in field-based team sports. PROSPERO registration number CRD42020200022.
The spectrum of GATA2 deficiency syndrome
Authors: Katherine R. Calvo, Dennis D. Hickstein
Journal: Blood (2022)

Inherited or de novo germ line heterozygous mutations in the gene encoding the transcription factor GATA2 lead to its deficiency. This results in a constellation of clinical features including nontuberculous mycobacterial, bacterial, fungal, and human papillomavirus infections, lymphedema, pulmonary alveolar proteinosis, and myelodysplasia. The onset, or even the presence, of disease is highly variable, even in kindreds with the identical mutation in GATA2. The clinical manifestations result from the loss of a multilineage progenitor that gives rise to B lymphocytes, monocytes, natural killer cells, and dendritic cells, leading to cytopenias of these lineages and subsequent infections. The bone marrow failure is typically characterized by hypocellularity. Dysplasia may either be absent or subtle but typically evolves into multilineage dysplasia with prominent dysmegakaryopoiesis, followed in some instances by progression to myeloid malignancies, specifically myelodysplastic syndrome, acute myelogenous leukemia, and chronic myelomonocytic leukemia. The latter 3 malignancies often occur in the setting of monosomy 7, trisomy 8, and acquired mutations in ASXL1 or in STAG2. Importantly, myeloid malignancy may represent the primary presentation of disease without recognition of other syndromic features. Allogeneic hematopoietic stem cell transplantation (HSCT) results in reversal of the phenotype. There remain important unanswered questions in GATA2 deficiency, including the following: (1) Why do some family members remain asymptomatic despite harboring deleterious mutations in GATA2? (2) What are the genetic changes that lead to myeloid progression? (3) What causes the apparent genetic anticipation? (4) What is the role of preemptive HSCT?
Single-cell atlases link macrophages and CD8<sup>+</sup> T-cell subpopulations to disease progression and immunotherapy response in urothelial carcinoma
Authors: Yuan Liang, Yezhen Tan, Bao Guan, Bin Guo, Mancheng Xia, Juan Li, Yue Shi, Zihui Yu, Qi Zhang, Di Liu, Xiaopeng Yang, Junfeng Hao, Yanqing Gong, Muhammad Shakeel, Liqun Zhou, Weimin Ci, Xuesong Li
Journal: Theranostics (2022)

Immune checkpoint inhibitors (ICIs) have revolutionized the management of locally advanced or metastatic urothelial carcinoma. Strikingly, compared to urothelial carcinoma of the bladder (UCB), upper tract urothelial carcinoma (UTUC) has a higher response rate to ICIs. The stratification of patients most likely to benefit from ICI therapy remains a major clinical challenge.
Mutant NPM1 Hijacks Transcriptional Hubs to Maintain Pathogenic Gene Programs in Acute Myeloid Leukemia
Authors: Xue Qing David Wang, Dandan Fan, Qinyu Han, Yiman Liu, Hongzhi Miao, Xinyu Wang, Qinglan Li, Dong Chen, Haley Gore, Pamela Himadewi, Gerd P. Pfeifer, Tomasz Cierpicki, Jolanta Grembecka, Jianzhong Su, Shasha Chong, Liling Wan, Xiaotian Zhang
Journal: Cancer Discovery (2022)

Abstract Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of biological functions. In 30% of acute myeloid leukemia (AML), the terminal exon of NPM1 is often found mutated, resulting in the addition of a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c). AMLs carrying this mutation have aberrant expression of the HOXA/B genes, whose overexpression leads to leukemogenic transformation. Here, for the first time, we comprehensively prove that NPM1c binds to a subset of active gene promoters in NPM1c AMLs, including well-known leukemia-driving genes—HOXA/B cluster genes and MEIS1. NPM1c sustains the active transcription of key target genes by orchestrating a transcription hub and maintains the active chromatin landscape by inhibiting the activity of histone deacetylases. Together, these findings reveal the neomorphic function of NPM1c as a transcriptional amplifier for leukemic gene expression and open up new paradigms for therapeutic intervention. Significance: NPM1 mutation is the most common mutation in AML, yet the mechanism of how the mutant protein results in AML remains unclear. Here, for the first time, we prove mutant NPM1 directly binds to active chromatin regions and hijacks the transcription of AML-driving genes. See related article by Uckelmann et al., p. 746. This article is highlighted in the In This Issue feature, p. 517
Targeting psychological stress-steroid-MARCH1 signaling pathway promotes the efficacy of specific allergen immunotherapy
Authors: Xiang He, Jie Liu, Xiaojun Xiao, Shuang Zhang, Xinxin Wang, Jiangqi Liu, Zhiqiang Liu, Junyi Wang, Xiaoyu Liu, Guoping Li, Pingchang Yang
Journal: Theranostics (2022)

Background:The therapeutic efficacy of allergen specific immunotherapy (SIT) is recognized, but needs improved.Psychological stress influences the immune system's function.The objective of this study is to elucidate the effects of psychological stress on compromising the effectiveness of SIT.Methods: A murine model with the airway allergic disorder (AAD) was established.Mice were treated with SIT with or without restraint stress (Rs).Results: Rs was found to significantly hamper the efficacy of SIT in mice with AAD.Induction of IL-10 + dendritic cells and type 1 regulatory T cells were reduced by Rs in the airway tissues.Rs-induced cortisol release subverted immune tolerance generation.Expression of MARCH1 was elevated in dendritic cells of the allergic lesion sites.The Rs-induced MARCH1 mediated the immune impairment in AAD mice.Genetic ablation of MARCH1 in dendritic cells efficiently blocked the Rs-compromised the therapeutic efficacy of SIT.Conclusion: Rs can increase the expression of MARCH1 in DCs of the allergic lesion sites.MARCH1 interferes with the immune regulatory properties in DCs, and impairs the immune regulatory capacity.Blocking MARCH1 can counteract the Rs-affected SIT efficacy.
Cellular therapy: Great promise, but at what cost?
Authors: Matthew G. Mei, Lisa Masucci, Michael D. Jain
Journal: Molecular Therapy (2022)

The introduction of chimeric antigen receptor T cell (CAR-T) therapy has been transformative in hematological malignancies. In the US, there are now 6 FDA-approved products across 5 malignancies; acute lymphoblastic leukemia, diffuse large B cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma, and multiple myeloma. These are highly potent treatments that are effective in patients that are highly pretreated and chemo-refractory and are likely curative in some cases. However, despite the fact that the first commercial CAR-T product (axicabtagene ciloleucel) received an FDA approval in October 2017, access to CAR-T remains challenging for myriad reasons including, but not limited to, expertise, infrastructure for apheresis and administration, manufacturing capacity, and cost. In particular, the cheapest CAR-T product is $373,000 USD. Even in a world where we have become accustomed to targeted therapies costing well over $10,000/month, these prices are extraordinarily high.